• Exclude patients with Philadelphia positive (Ph +ve) ALL • Native E. coli asparaginase replaced by Oncaspar, a peglated form of L-asparaginase with fewer side effects.

• Inclusion of patients who have had more than one relapse of their leukaemia • Inclusion of patients who are philadelphia positive (Ph+ve) who have failed previous treatment with TK1 • Inclusion of patients who have had prior mediastinal radiotherapy • Changes to Principal Investigators and sites

change from intensive to less intensive chemotherapy removal of daunorubicin; removal of cardiac MRI and ECG; removal of upper age limit; inclusion of patients who have had more than one relapse; inclusion of patients who have had prior radiotherapy Change of CI: Prof. Andrew Lister to Prof. Matthew Smith

• Changes to Principal Investigators and sites

-Amended timeframe of lumbar puncture and bone marrow samples during screening and addition of collection of bone marrow for research at screening, -Extended study duration, Inclusion of refractory patients, reduce time limit since previous antibody therapy, -Addition of new sites

• Changes to inclusion criteria  Include refractory patients.  Amend the current definition of refractory patients.  Requirement that patients should have greater than or equal to 5% blasts in the marrow. • Changes to exclusion criteria  Allowing patients to have received corticosteroids for the current relapse episode for a maximum of 10 days rather than 5.  Positive antinuclear antibody (ANA) test.  Change of exclusion of patient receiving antibody therapy in the last 9 months to last 3 months in line with recommendations from Immunomedics. • Addition of ANA testing to study schedule and medical examinations and laboratory assessments at screening and Day 29 • Removal of option to provide peripheral blood rather than bone marrow for the MRD test in this protocol to make bone marrow an absolute requirement. • Changes to preparation and administration of Veltuzumab and epratuzumab in line with new administration guidelines from Manufacturer (Immunomedics). • Removal of IMP status of Vincristine, PEG-Asparaginase (OncasparR), Dexamethasone, Methotrexate and Erwinia Asparaginase (ErwinaseR) (now NIMPs) which are standard chemotherapy for ALL patients. • Change to timing of administration of pre-medication from 15-30mins to 30-60mins before administration of epratuzumab or veltuzumab to reduce risk of hypersensitivity in line with Immunomedics guidelines. • Change of Route of administration of PEG-Aspariginase from IV to IV or IM to ensure consistency in protocol document and in line with SmPC.

Changes to inclusion and exclusion criteria, and addition of ANA testing.

NB: Urgent Safety Measure In light of signals of liver toxicity being experienced by some patients, the DMC was convened. This toxicity was attributed to the PEG-Asparaginase (nIMP) component of the chemotherapy back bone. Committee recommended an USM be implemented which prescribes changes to the dose of PEG-Asparaginase (nIMP) based on patient disease status, age and any conmeds/comorbidity. These are summarised below: 2 doses of asparaginase – Day 4 and Day 18 • Patients who are being treated with curative intent - this will typically be younger, fitter patients in first relapse heading for an allograft procedure in CR2 • If patients in this group suffer >grade 2 liver toxicity after the first dose of asparaginase, the second dose, on Day 18, should be omitted. 1 dose of asparaginase – Day 18 • Those patients who do not fit into either above or below category, at physician’s discretion. 0 doses of asparaginase • Over 60 years of age. • Philadelphia positive on TKIs. • On third line therapy. • Have chronic/underlying liver co-morbidities, including but not limited to liver GVHD or a history of liver disease. • Grade 2 Baseline LFTs. To ensure that these safety measures are effective, mandated expedited reporting of all liver toxicity of grade 3 and grade 4 with a further review of safety data after 10 patients have been recruited to Cohort C of the trial.

Urgent safety measure - changes to the dose of PEG-Asparaginase (NIMP) based on patient disease status, age and any concomitant medications/ co morbidity. The expedited reporting of all liver toxicity of grade 3 and grade 4 was additionally mandated in this amendment.